Regulation of interleukin-1 and tumor necrosis factor-α induced granulocyte-macrophage colony-stimulating factor gene expresion: Potential involvement of arachidonic acid metabolism

M. T. Rizzo, H. Boswell

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17 Citations (Scopus)

Abstract

Signal transduction pathways evoked by interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) to stimulate expression of other cytokines in mesenchymal cells are not clearly understood. Stimulation of the murine bone marrow stromal cell line +/+-LLDA 11 with IL-1 (500 U/ml) in combination with TNF-α (500 U/ml) (IL-1 plus TNF-α) induced expression of c-jun mRNA as well as granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA. We investigated the possibility that arachidonic acid metabolites, acting through protein kinase C (PKC) and perhaps also through the PKC-responsive transcription factor c-jun/AP-1, may be responsible for regulating GM-CSF transcription in these stromal cells. Expression of GM-CSF mRNA was preceded by IL-1 plus TNF-α induced arachidonate release (assayed using the 3H- derivative). Pretreatment of cells with the phospholipase A2 inhibitor quinacrine (20 μM) inhibited accumulation of both c-jun and GM-CSF mRNA, but had no influence on expression of other genes induced by IL-1 and TNF-α, including leukemia inhibitory factor (LIF). In addition, quinacrine partially blocked IL-1 plus TNF-α induced 3H-arachidonic acid release from prelabeled stromal cells. Furthermore, exogenous arachidonate (10 to 50 μM) induced expression of c-jun. To investigate the role of arachidonate in GM-CSF transcription, we used a reporter vector consisting of the murine GM-CSF promoter linked to firefly luciferase. Transfection efficiency was monitored by assessing expression of a constitutively active gene, RSV-β galactosidase. In this system, quinacrine significantly inhibited IL-1 plus TNF-α induced GM-CSF transcription assayed with the reporter construct. Exogenous arachidonic acid alone (10 μM) increased activity of GM-CSF reporter vector 1.5-fold over control. These results are consistent with the hypothesis that arachidonate metabolites are involved in the signaling pathway that leads to IL-1 plus TNF-α induced GM-CSF gene expression. Thus, transcriptional activation of GM-CSF gene is mediated, in part, by the arachidonate cascade.

Original languageEnglish
Pages (from-to)87-94
Number of pages8
JournalExperimental Hematology
Volume22
Issue number1
StatePublished - 1994

Fingerprint

Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-1
Arachidonic Acid
Tumor Necrosis Factor-alpha
Genes
Quinacrine
Messenger RNA
Stromal Cells
Protein Kinase C
Galactosidases
Firefly Luciferases
Leukemia Inhibitory Factor
Gene Expression
Transcription Factor AP-1
Mesenchymal Stromal Cells
Transcriptional Activation
Transfection
Signal Transduction
Transcription Factors
Cytokines

Keywords

  • Arachidonic acid
  • GM-CSF
  • IL-1
  • Quinacrine
  • TNF-α

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

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title = "Regulation of interleukin-1 and tumor necrosis factor-α induced granulocyte-macrophage colony-stimulating factor gene expresion: Potential involvement of arachidonic acid metabolism",
abstract = "Signal transduction pathways evoked by interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) to stimulate expression of other cytokines in mesenchymal cells are not clearly understood. Stimulation of the murine bone marrow stromal cell line +/+-LLDA 11 with IL-1 (500 U/ml) in combination with TNF-α (500 U/ml) (IL-1 plus TNF-α) induced expression of c-jun mRNA as well as granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA. We investigated the possibility that arachidonic acid metabolites, acting through protein kinase C (PKC) and perhaps also through the PKC-responsive transcription factor c-jun/AP-1, may be responsible for regulating GM-CSF transcription in these stromal cells. Expression of GM-CSF mRNA was preceded by IL-1 plus TNF-α induced arachidonate release (assayed using the 3H- derivative). Pretreatment of cells with the phospholipase A2 inhibitor quinacrine (20 μM) inhibited accumulation of both c-jun and GM-CSF mRNA, but had no influence on expression of other genes induced by IL-1 and TNF-α, including leukemia inhibitory factor (LIF). In addition, quinacrine partially blocked IL-1 plus TNF-α induced 3H-arachidonic acid release from prelabeled stromal cells. Furthermore, exogenous arachidonate (10 to 50 μM) induced expression of c-jun. To investigate the role of arachidonate in GM-CSF transcription, we used a reporter vector consisting of the murine GM-CSF promoter linked to firefly luciferase. Transfection efficiency was monitored by assessing expression of a constitutively active gene, RSV-β galactosidase. In this system, quinacrine significantly inhibited IL-1 plus TNF-α induced GM-CSF transcription assayed with the reporter construct. Exogenous arachidonic acid alone (10 μM) increased activity of GM-CSF reporter vector 1.5-fold over control. These results are consistent with the hypothesis that arachidonate metabolites are involved in the signaling pathway that leads to IL-1 plus TNF-α induced GM-CSF gene expression. Thus, transcriptional activation of GM-CSF gene is mediated, in part, by the arachidonate cascade.",
keywords = "Arachidonic acid, GM-CSF, IL-1, Quinacrine, TNF-α",
author = "Rizzo, {M. T.} and H. Boswell",
year = "1994",
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T1 - Regulation of interleukin-1 and tumor necrosis factor-α induced granulocyte-macrophage colony-stimulating factor gene expresion

T2 - Potential involvement of arachidonic acid metabolism

AU - Rizzo, M. T.

AU - Boswell, H.

PY - 1994

Y1 - 1994

N2 - Signal transduction pathways evoked by interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) to stimulate expression of other cytokines in mesenchymal cells are not clearly understood. Stimulation of the murine bone marrow stromal cell line +/+-LLDA 11 with IL-1 (500 U/ml) in combination with TNF-α (500 U/ml) (IL-1 plus TNF-α) induced expression of c-jun mRNA as well as granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA. We investigated the possibility that arachidonic acid metabolites, acting through protein kinase C (PKC) and perhaps also through the PKC-responsive transcription factor c-jun/AP-1, may be responsible for regulating GM-CSF transcription in these stromal cells. Expression of GM-CSF mRNA was preceded by IL-1 plus TNF-α induced arachidonate release (assayed using the 3H- derivative). Pretreatment of cells with the phospholipase A2 inhibitor quinacrine (20 μM) inhibited accumulation of both c-jun and GM-CSF mRNA, but had no influence on expression of other genes induced by IL-1 and TNF-α, including leukemia inhibitory factor (LIF). In addition, quinacrine partially blocked IL-1 plus TNF-α induced 3H-arachidonic acid release from prelabeled stromal cells. Furthermore, exogenous arachidonate (10 to 50 μM) induced expression of c-jun. To investigate the role of arachidonate in GM-CSF transcription, we used a reporter vector consisting of the murine GM-CSF promoter linked to firefly luciferase. Transfection efficiency was monitored by assessing expression of a constitutively active gene, RSV-β galactosidase. In this system, quinacrine significantly inhibited IL-1 plus TNF-α induced GM-CSF transcription assayed with the reporter construct. Exogenous arachidonic acid alone (10 μM) increased activity of GM-CSF reporter vector 1.5-fold over control. These results are consistent with the hypothesis that arachidonate metabolites are involved in the signaling pathway that leads to IL-1 plus TNF-α induced GM-CSF gene expression. Thus, transcriptional activation of GM-CSF gene is mediated, in part, by the arachidonate cascade.

AB - Signal transduction pathways evoked by interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) to stimulate expression of other cytokines in mesenchymal cells are not clearly understood. Stimulation of the murine bone marrow stromal cell line +/+-LLDA 11 with IL-1 (500 U/ml) in combination with TNF-α (500 U/ml) (IL-1 plus TNF-α) induced expression of c-jun mRNA as well as granulocyte-macrophage colony stimulating factor (GM-CSF) mRNA. We investigated the possibility that arachidonic acid metabolites, acting through protein kinase C (PKC) and perhaps also through the PKC-responsive transcription factor c-jun/AP-1, may be responsible for regulating GM-CSF transcription in these stromal cells. Expression of GM-CSF mRNA was preceded by IL-1 plus TNF-α induced arachidonate release (assayed using the 3H- derivative). Pretreatment of cells with the phospholipase A2 inhibitor quinacrine (20 μM) inhibited accumulation of both c-jun and GM-CSF mRNA, but had no influence on expression of other genes induced by IL-1 and TNF-α, including leukemia inhibitory factor (LIF). In addition, quinacrine partially blocked IL-1 plus TNF-α induced 3H-arachidonic acid release from prelabeled stromal cells. Furthermore, exogenous arachidonate (10 to 50 μM) induced expression of c-jun. To investigate the role of arachidonate in GM-CSF transcription, we used a reporter vector consisting of the murine GM-CSF promoter linked to firefly luciferase. Transfection efficiency was monitored by assessing expression of a constitutively active gene, RSV-β galactosidase. In this system, quinacrine significantly inhibited IL-1 plus TNF-α induced GM-CSF transcription assayed with the reporter construct. Exogenous arachidonic acid alone (10 μM) increased activity of GM-CSF reporter vector 1.5-fold over control. These results are consistent with the hypothesis that arachidonate metabolites are involved in the signaling pathway that leads to IL-1 plus TNF-α induced GM-CSF gene expression. Thus, transcriptional activation of GM-CSF gene is mediated, in part, by the arachidonate cascade.

KW - Arachidonic acid

KW - GM-CSF

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KW - TNF-α

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